J. Mex. Chem. Soc. 2005, 49(2), 229-238.
© 2005, Sociedad Química de México
J. Braz. Chem. Soc., Vol. 16, No. 3A, 467-476, 2005.
© 2005, Sociedade Brasileira de Química
0103 - 5053
,a
a
b
c
Federico García-Jiménez* , Ofelia Collera Zúñiga , Yolanda Castells García , Julio Cárdenas and
,a
Gabriel Cuevas*
a
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria 04510,
Coyoacán, México D.F., México
b
Escuela Nacional Preparatoria, Universidad Nacional Autónoma de México, Plantel Antonio Caso,
Coyoacán, 04500 México D.F., México
c
Escuela de Ciencias Químicas, Universidad La Salle, Benjamín Franklin 47, Hipódromo Condesa,
06140 México D.F., México
A estrutura molecular predominante para o DL e para o D-gliceraldeído foi estudada utilizando
espectroscopia de infravermelho e de ressonância magnética nuclear. As duas técnicas mostraram
que, a temperatura ambiente, estes compostos apresentam apenas uma pequena porcentagem da
forma aldeído. Estes estudos mostraram que a forma aldeído para o D-(+)-gliceraldeido coexiste,
como componente em pequena proporção, com uma mistura complexa de diastereosômeros do 2,5di-hidroxi-3,6-di-hidroximetil-1,4-dioxano, enquanto a mistura racêmica é constituída por dois
compostos principais. A estabilidade dos diasteroisômeros é controlada pela formação de ligações de
hidrogênio intramoleculares em decorrência do efeito anomérico, que define a posição favorável para
o grupo hidroxila. As interações anoméricas endo e exo são originadas pela interação estereoeletrônica
nO → σ*C-O. Utilizando cálculos teóricos em nível B3LYP/6-31G(d,p) foi possível estabelecer a
estrutura dos confôrmeros favorecidos.
The predominant molecular structure of DL and D-glyceraldehyde has been studied with infrared
and nuclear magnetic resonance spectroscopies. Both techniques show that these compounds at
room temperature have a minor percentage of the aldehydic form. These studies showed that D-(+)glyceraldehyde coexists in a minor proportion as a component of a complex mixture of diasteroisomers
of the 2,5-dihydroxy-3,6-dihydroxymethyl-1,4-dioxane, while the racemic mixture is made of two
main compounds. The stability of the isolated diasteroisomers is controlled by the formation of
intramolecular hydrogen bonds that are formed under the control of the anomeric effect which
defines the favored position for the hydroxyl group. The endo and exo-anomeric interactions have
their origin in the stereoelectronic interaction nO → σ*C-O. Using theoretical calculations at B3LYP/
6-31G(d,p) level, it was possible to establish the structure of the favored conformers.
Keywords: DL-glyceraldehyde, D-glyceraldehyde, 1,4-dioxanes, nuclear magnetic resonance,
density functional calculations, stereoelectronic effects, anomeric effect, hydrogen bond, weak interactions
Introduction
The so-called weak interactions are fundamental in the
development of emerging areas of Chemistry such as
Supramolecular Chemistry and Crystal Engineering. These
interactions are also of great importance in the molecular
recognition that controls biological functions, so it is
paramount to understand their origin, establish their
magnitude and the factors that modify them. In this study,
* e-mail: fedgar@servidor.unam.mx , gecgb@servidor.unam.mx
we selected for the analysis glyceraldehyde, a molecule
where several types of these interactions coexist and affect
molecular energy.
D-glyceraldehyde is without any doubt one of the most
important compounds in the fields of chemistry,
biochemistry and biology. It is the first carbohydrate
produced by most plants in photosynthesis as 3phosphoglycerate.1 Most chemists and biochemists are
familiar with the D- and L- molecular structures of
glyceraldehydes which appear in Chemistry and
Article
Experimental and Theoretical Study of the Products from the Spontaneous Dimerization
of DL- and D-Glyceraldehyde
230
García-Jiménez et al.
Biochemistry textbooks,2 and is the reference to establish
the absolute stereochemistry of all chemical compounds
with which it is directly or indirectly correlated.3 However
if the infrared technique is used to evaluate a sample of
commercial glyceraldehyde, it is impossible to find a
strong infrared band for an aldehyde function as the name
implies. In the case of DL-glyceraldehyde the possibility
of a polymerization by hemiacetalization was already
mentioned by Wohl4 in the first reported synthesis of this
compound. Later Wohl and Neuberg 5 proposed the
formation of cyclic dimeric hemiacetal for DLglyceraldehyde. In D2O solution of DL-glyceraldehyde it
has been found that the intensity of the band associated
with the carbonyl group increases as the temperature
increases.6 The percentage of free D-glyceraldehyde has
been estimated as 9.8% and 4.4% using infrared (at 1729
cm–1) and the ultraviolet (273 nm) confirm the presence of
a carbonyl group in low concentration.7 Purification by
means of activated carbon does not modify these results.
DL-glyceraldehyde-3-phosphate shows similar results.
The trimethylsilyl derivative of DL-glyceraldehyde has
also been shown to correspond to the dimeric cyclic
hemicetal using NMR spectroscopy.8
Figure 1. Dimerization of glyceraldehyde.
There is also an increase of the enolic form of the
aldehyde which may lead to some transformation into
hydroxyacetone when the temperature increases. Since this
process is reversible it may also lead to racemization.4 In
the case of dihydroxyacetone there is also formation of
cyclic dimers but the proportion of the dimeric form is
low.7
Results
DL-glyceraldehyde and D-glyceraldehyde were studied
using Infrared spectroscopy together with 13C and 1H
nuclear magnetic resonance. In the case of commercial
DL-glyceraldehyde 1% or less of the free carbonyl band
according to the intensity in the solid state was found.
This is in agreement with the information from both 13C
and 1 H nuclear magnetic resonance. In contrast
D-glyceraldehyde, shows 10 ± 0.2% of the free carbonyl
as determined from the intensity of the carbonyl band at
J. Braz. Chem. Soc.
1731 cm–1 we also observed an enol band at 1643 cm–1.5
This information is in agreement with the information from
13
C and 1H nuclear magnetic resonance (in 1H resonance
there is a doublet centered at 9.61 ppm for an aldehyde
proton and in 13C resonance a signal appear at 204.6 ppm
for the carbonyl function).
Determination of the hemiacetal dimeric structure of DLand D-glyceraldehyde
First the solid DL-glyceraldehyde was studied. The 13C
NMR of this compound is rather simple, it shows only
three main signals at 92.4 ppm for 2-C(2,5) (Figure 1). A
signal at 78.9 ppm for carbon C(3,6) in a dioxane ring and
finally a signal at 60.5 ppm for a hydroxymethylene
moiety. The system must have high symmetry since it
shows only three signals for six carbon atoms. The 1H NMR
of this compound in DMSO-d6 is also relatively simple. It
shows only one doublet (6.72 and 6.70 ppm) for two protons
at the oxygen atom of two hydroxyl groups in two dioxane
carbons (C1 in glyceraldehyde), which in turn have one
proton each at 4.5 ppm showing also couplings with two
symmetrically placed protons at about 3.2 ppm on the
dioxane ring (C2 in glyceraldehyde). The OH proton in
the hydroxymethylene groups gives a triplet and is coupled
to a gem AB system of the hydrogens at the
hydroxymethylenes which show a multiplet between 3.6
and 3.3, also coupled with the protons at 3.2 ppm. Both
NMR spectra (13C and 1H) show slight modification which
include the appearance of additional peaks, indicating
stability between 20 and 80 °C.
The data above correspond to a highly symmetrical
substituted 1,4-dioxane dimeric hemiacetal. The structure
includes very strong intramolecular hydrogen bonds since
the 1H NMR spectra show only slight modifications
between 20 and 80 °C. This structure has specific
stereochemistry and during its formation two new
asymmetric centers are induced in a natural regio-specific
synthesis. Commercial DL-glyceraldehyde is thus not an
epimeric mixture, but produces an epimeric hemicetal by
spontaneous dimerization.
In the case of the commercial D-glyceraldehyde, the
13
C shows a large number of peaks instead of the simple
patterns for the DL-glyceraldehyde. One of the peaks is at
204.6 ppm and is assigned to the carbon atom in a carbonyl
function of glyceraldehydes. Other 16 peaks are seen even
after eliminating small peaks, which may be attributed to
free glyceraldehydes hydrates. The large number of peaks
may be attributed to different combinations of dimeric
stereoisomers and other different conformers and hydrates
(see below). The region between 104.5 and 90.2 ppm may
J. Mex. Chem. Soc.
Experimental and Theoretical Study of the Products from the Spontaneous Dimerization
be assigned to the presence of carbon atoms of hemicetal
type and shows 18 signals. This may be assigned to the
three main stereoisomers in different conformations. We
also have to remember that one of the differences between
DL- and D-glyceraldehyde is the level of hydration which
in the last case amounts to about 0.17 mol of water per mol
of the aldehyde and in the first case is almost absent.
Between 83.5 and 77.5 ppm there are six main signals
which correspond to carbon at position 3 and 6 of the
dioxane ring (C2 of the glyceraldehyde) this agree with
three main stereoisomers, this particular atom does not
have hydroxyl or hydroxymethylene groups and will not
change very much because of differences in hydrogen
bonding. Finally, between 73.9 and 59.4 ppm we find 24
peaks which correspond to the hydroxymethylene carbon.
This carbon shows the highest possibility of forming
different conformations and combinations of hydrogen
bonding including those with a molecule of water. The 1H
NMR is also very complex showing a signals for an
aldehyde group at 9.620 and 9.617 ppm its integration is
barely noticeable. Between 6.55 and 6.34 ppm there is a
series of doublets corresponding to the OH group at C-2
and C-4 of a dioxane ring; six of them are most noticeable,
further doublets are seen between 6.06 and 5.79 and
between 5.61 and 5.41 ppm. Between 3.98 and 3.13 ppm
there is a complex multiplet signal. The signal appear in
the same region as for DL-glyceraldehyde but the pattern
is much more complicated because of the presence of many
dimeric hemicetal isomers and conformers as well as by
the presence of different hydrates.
Computational study
When the R enantiomer of glyceraldehyde (1, Figure
1) is dimerized, it can lead the ring of 1,4-dioxane through
the attack of the hydroxyl group at position 2 to any of the
proquiral phases of the carbonyl group perhaps following
the path according to by Cram’s model.9 Four possible
stereoisomers of 2,5-dihydroxy-3,6-dihydroxymethyl-1,4dioxane can be generated (2, Figure 1) and are presented
in equations 1 to 4. When the racemic mixture is studied,
in other words from the equimolecular mixture of the R
and S enantiomers, four new additional diasteroisomers
can be produced (equations 5 to 8) and of course their
corresponding enantiomers. In summary, a total of 16
possible diasteroisomers are obtainded, 8 pairs of
enantiomers.
Thus, the stereogenic centers at positions 3 and 6 are
defined by the original configuration of glyceraldehydes
(only series R will be addressed here) while those at
positions 2 and 4 (anomeric positions) are defined when
231
the condensation that originates dioxane takes place. Each
one of these diasteroisomers presents two possible
conformational arrangements due to the ring inversion of
1,4-dioxane.10 Since the chair conformer is known to be
the most stable arrangement of 1,4-dioxane, this study will
only address this type. In each arrangement, the different
type of interactions that affects the molecular stability is
investigated.
From previous studies,11 it is possible to conclude that
the endo and exo-anomeric effect is the factor that
influences the stability of 2-methoxy-oxane, thus, these
effects should show in the stability of the stereoisomers of
interest. Hydrogen bonds are of more importance due to
their stabilizing capacity. The hydroxymethyl group can
be involved and restrict their degrees of conformational
freedom. Four types of hydrogen bonds can be expected;
the hydrogen bonds where the OH group on the anomeric
position is the donor and the hydroxymethyl the acceptor
(for example equation 1); those where this relationship is
inverted (for example, conformers 9 and 13 of equation 4);
those where the hydroxyl group is the donor and the annular
oxygen is the acceptor (7, equation 4); and finally, those
formed by three groups where the anomeric hydroxyl group
is both, the donor and the acceptor (10, equation 3).
Equations 1 through 4 show four conformational
equilibria of four diasteroisomers for compound 2
generated by the dimerization of the R enantiomer of
glyceraldehyde (for all equations total energy is in Hartrees
and relative energy in kcal/mol). On equation 1 2R,5Rdihydroxy-3R,6R-dihydroxymethyl-1,4-dioxane, hereon
referred to as RRRR-(2), where the configuration of the
stereogenic centers corresponds to the 2,3,5 and 6 positions,
respectively.
(1)
At B3LYP/6-31G(d,p) level, conformer 1 is 2.21 kcal/
mol more stable than conformer 2. In conformer 1 the
hydroxyl group at position 2 participates as a donor of
hydrogen bond to the hydroxymethyl group at position 3.
Since it occupies the equatorial position, it cannot be
favored by the endo-anomeric interaction,12 but it can be
by the exo-anomeric, even when the hydrogen atom does
232
García-Jiménez et al.
not adopt the optimal position from the stereoelectronic
point of view in order to favor the formation of an hydrogen
bond. In contrast, the hydroxyl group at position 5 can
benefit of the endo-anomeric interaction but not by the
exo-anomeric one because the hydrogen atom occupies
that position to form the hydrogen bond with the
hydroxymethyl group. In conformer 2 the hydroxyl group
at position 2 is benefited only by the endo-anomeric (nOendo
→ σ*C-O) interaction while the hydroxyl group at position
5 is only benefited by the exo-anomeric (nOexo → σ*C-O)
interaction.12,13 This sets-up a certain balance in terms of
the stereoelectronic interactions among compounds 1 and
2. However, the hydroxyl at position 5 is now the acceptor
in the formation of the hydrogen bond and not the donor
like the hydroxyl at position 2. This allows for the
establishment of the most stabilizing contribution of the
hydrogen bonds that is produced when the atom that
participates in a stereoelectronic interaction is also the
donor in the hydrogen bond.
On equation 2 two conformers of the compound of
configuration RRSR-2 are presented. On conformer 3 the
hydroxyl groups are equatorial, so they are not benefited
by the nOendo → σ*C-O interaction and the antiperiplanar
disposition of the O-H bond in relation to the C5-O bond
may point out that the nOexo → σ*C-O interaction cannot
occur, but in some manner is substituted by the σH-O →
σ* C-O interaction. This disposition of less stabilizing
capability is due to the formation of an hydrogen bond
where this group is the donor to the hydroxylmethyl group
at position 6. The hydroxyl group at position 2 is also a
donor of the hydrogen bond, that persists in conformer 4
where the group is benefited by the n Oendo → σ* C-O
interaction and forms a second hydrogen bond as acceptor
of the hydroxymethyl group at position 6. On the other
hand, the hydroxyl group at position 5 is benefited by the
nOendo → σ*C-O an nOexo → σ*C-O interactions. Conformer 4
that combines two hydrogen bonds where the hydroxyl
group is the donor and acceptor of the hydrogen bond and
the hydroxyl groups in axial position that are favored by
the anomeric effect, is 3.18 kcal/mol more stable than the
conformer that presents two independent hydrogen bonds
and lacks the stabilizing benefit of the anomeric effect.
(2)
J. Braz. Chem. Soc.
Equation 3 presents a pair of conformers of the
diasteroisomer with SRSR configuration. On conformer 5,
the trans-diaxial nature of the groups at positions 2 and 3
block the mutual formation of hydrogen bonds. Because
the hydroxyl at position 5 is equatorial it cannot form a
bond like the one formed in conformer 4, but the formation
of a hydrogen bond with the hydroxymethyl group on
position 6 is favored. The hydroxyl group at position 2 is
benefited from the endo and exo nO → σ*C-O interactions
but it is important to point out that the hydrogen atom of
the hydroxyl group points toward the center of the ring,
position that produces stabilization due to the fact that it
allows the interaction of one of the unshared electron pairs
of the oxygen atom with the C-O antibond.
(3)
Conformer 6 maintains all the interactions shown by
5, except for the hydrogen atom of the axial hydroxyl
group which is gauche in relation to the C-O bond pointing
to the outside of the ring. This shows that the hydrogen
atom of conformer 5 provokes a stabilizing effect of 0.74
kcal/mol compared to conformer 6.
To properly evaluate the effect of the hydrogen bondtype, several dispositions of these were evaluated in different
conformers of the SRRR diasteroisomer (equation 4).
On the series of conformers 7 to 10, the axial hydroxyl
group at position 2 maintains the hydrogen atom pointing
towards the center of the ring and favoring two of the endo
and exo-anomeric interactions. On conformer 11 the O-H
bond was placed in gauge position in relation to the O-C2
bond, maintaining the same disposition of the other
substituents. The fact that this conformer is at 0.89 kcal/
mol over conformer 10, confirms the stabilizing nature of
the OH orientation towards the center of the ring.
On conformer 10, the most stable of the series of
conformers shown in equation 4, the hydroxyl group at
position 5 also stays in axial position and participates in
the formation of two hydrogen bonds. It is an acceptor in
relation to the hydroxymethyl group at position 3 and is a
donor in relation to the hydroxymethyl group at position
6. In this disposition, the O-H bond is antiperiplanar to the
C5-O bond, so if it participates in the σH-O → σ*C-O
stereoelectronic interaction, the resonance hybrid would
J. Mex. Chem. Soc.
233
Experimental and Theoretical Study of the Products from the Spontaneous Dimerization
(4)
make the hydrogen atom a better donor in the hydrogen
bond and the oxygen would be a better acceptor. The
stereoelectronic interaction would increase the tendency
for the hydrogen bond formation. On conformer 9 the
disposition of the unshared electron pairs is altered
maintaining the hydroxyl group at position 5 as a
participant of both bonds, but eliminating the
stereoelectronic interactions as factors that accentuate the
acidity of the proton in question. The energy increases
3.95 kcal/mol in relation to 10. On conformer 8 where the
anomeric hydroxyl at position 5 is acceptor of both
hydrogen bonds formed with the hydroxymethyl groups,
the energy is increased 6.70 kcal/mol. In conformer 7,
where one of the hydrogen bonds is broken by the rotation
of the hydroxymethyl group only one bonds is maintained
increasing the donor capacity of the C5 hydroxyl through
the σH-O → σ*C-O interaction. This produces an increase of
5.53 kcal/mol in relation to conformer 10.
On the series of conformers 12-14 the hydroxyl groups
adopt the equatorial conformation losing the stabilization
given by the endo-anomeric effect. Conformer 12 is 2.93
kcal/mol less stable than conformer 13. These two
conformers only differ in the fact that in 12 the hydroxyl
group at position 2 is the donor of the hydrogen bond
while in 13 it is the acceptor. The electronic arrangement
on 13 allows the participation of the nOexo → σ*C-O effect.
In conformer 14 the nO → σ*C-O stereoelectronic interaction
is blocked just as on 12 but the change of the donor group
of the hydrogen bond between the groups at positions 5
and 6 does not substantially affect the exo-anomeric
interaction by allowing the disposition of one unshared
electron pair in antiperiplanar arrangement to the C5-O
bond.
The four diasteroisomers that, in addition to those
presented before, are formed when a racemic mixture of the
glyceraldehydes is studied (in addition to their corresponding enantiomers) are shown in equations 5 to 8.
The diasteroisomer of configuration RRRS-2 and some
of its conformers are presented in equation 5. The most
stable conformer (16) allows the exo-anomeric interaction
of the hydroxyl at position 2 that is the acceptor of the
hydrogen bond that forms with the hydroxymethyl group
at position 3. This is the most stabilizing arrangement of
the hydrogen bond according to the observation on the
SRRR-2 diasteroisomer. The hydroxyl group at position 5
shows an anomeric effect with the stabilizing arrangement
where the hydrogen atom points toward the center of the
ring just as it was shown for conformers 7 to 10 (equation
4). Curiously, the hydroxymethyl group at position 6 is
isolated. Conformer 17 is at 0.70 kcal/mol in relation to
16. Here the equatorial hydroxyl group at C2 is the acceptor
of the hydrogen bond. The endo- and exo-anomeric effect
experienced by the O-H at position 2 and the exo-anomeric
(5)
234
García-Jiménez et al.
at position 5 should contribute importantly to its
stabilization.
On conformer 15 several stabilizing interactions are
destroyed. The hydroxyl at C5 forms the only hydrogen
bond of the system with hydroxymethyl group at C3 and
energy increases 4.53 kcal/mol in relation to 16. On 18 the
only change is the donor of the hydrogen bond on segment
C2-C3 of the ring in relation to 17 and the energy is slightly
increased. This is different from what was observed in
equation 2. The change of donor of the hydrogen bond
between the substituents at positions 5 and 6 increases the
energy in 2.53 kcal/mol of 19 in relation to 18. On this
case, one of the unshared electron pairs of the oxygen
atom is substituted by the O-H bond. The nOexo → σ*C-O
interaction is more efficient than σ H-C → σ* C-O, and
originates, at least in part the observed destabilization.
Finally, the rotation of the hydroxymethyl group on
conformer 20 provokes the loss of the hydrogen bond with
the recovery of the nOexo → σ*C-O interaction. This increases
the energy by 4.63 kcal/mol in relation to 16, but only by
1.13 kcal/mol in relation to 19, because it loses the
hydrogen bond, but recovers the stereoelectronic
interaction.
Three of the conformers of diasteroisomer RRSS-2 are
shown on equation 6. The most stable (23) presents both
hydroxyl groups in axial position participating in the
formation of hydrogen bonds. Diasteroisomer 22 is at 0.52
kcal/mol and differs in relation to 23 in the fact that both
anomeric hydroxyls are donors of hydrogen bonds
attenuating the exo-anomeric interaction by substituting
it by an interaction where the donor is the O-H bond.
Conformer 21 is at 3.35 kcal/mol in relation to 23, because
it has lost the anomeric interactions and the hydroxyls
that maintain the hydrogen bonds with the hydroxymethyl
groups do not participate in the exo-anomeric effect.
(6)
The SRRS-2 diasteroisomer 24 (equation 7) is the most
stable of all the molecules studied here, and it is, of course,
the one where all interactions are constructive. This case
shows, again, the additivity of stereoelectronic
J. Braz. Chem. Soc.
interactions.14 On this conformer the hydroxyl groups at
anomeric positions are benefited from the endo and exoanomeric interactions. Also, they participate as donors of
hydrogen bonds with the hydroxymethyl groups at
positions 3 and 6 that are too hydrogen bond donors with
endocyclic oxygen atoms. The change in the donating
hydroxyl on conformer 25 causes the loss of the hydrogen
bond with the oxygen atom that forms part of the ring
causing an increase of almost 10 kcal/mol. On conformer
26 (equation 7) the loss of stability originated by the
anomeric effect causes an energy increase of 8.03 kcal/
mol even when the two hydrogen bonds where the
anomeric hydroxyl is the donor are preserved.
(7)
Finally, the diasteroisomer with SRSS-2 configuration
(equation 8) was analyzed. The most stable conformer of
the series has the axial hydroxyl in possibility to stabilize
the molecule with the participation of the nOendo → σ*C-O
and nOexo → σ*C-O interactions. In addition, it forms an
hydrogen bond with the hydroxymethyl at position 6. The
hydroxyl at position 2 can participate in the σH-O → σ*C-O
interaction because the hydrogen atom participates in the
formation of an hydrogen bond with the hydroxyl group
at position 2. The system where the donor of the hydrogen
bond in segment C5-C6 changes (30) is located at 2.94
kcal/mol in relation to 31. Now the exo-anomeric
interaction is lost. If this new hydrogen bond is maintained
and the donor atom is modified in the segment C2-C3,
conformer 29 is reached. Now, the C2 hydroxyl can
participate in the nOexo → σ*C-O interaction, but the energy
increases 7.79 kcal/mol in relation to 31. Conformers 27
and 28 show substituents C2 and C3 in trans-diaxial
position allowing the hydroxyl at position 2 of conformer
27 to benefit from n Oendo → σ* C-O and nOexo → σ* C-O
interactions in addition to forming a hydrogen bond as
donor with the hydroxymethyl group at position 6. This
hinders the stabilization of the system by hydroxyl group
at C5 with hydrogen bond-type interactions and
substantially increases the energy. On conformer 28 the
change of donor atom of the C2-C6 hydrogen bond causes
the loss of the nOexo → σ*C-O interaction leading to an
energy increase of 10.79 kcal/mol in relation to 31.
J. Mex. Chem. Soc.
Experimental and Theoretical Study of the Products from the Spontaneous Dimerization
(8)
From the different conformers analyzed in their different
conformations, it can be established that the compound
with structure 24 is the compound determined by NMR
due to its high symmetry presenting among other elements,
a point of symmetry. In addition, it presents two types of
hydrogen bonds just as determined by infrared analysis.
The Erel value present in equations 1 to 8 refers to the
energy of each isomer in relation to this all-axial
compound. With exception of conformer 10 that is located
at 0.73 kcal/mol over it, there are no possibilities of any
other conformer participating in the equilibria from the
population point of view.
Using NBO15 analysis, it is possible to determine the
energy of both interactions, nOexo → σ*C-O and nOendo →
σ*C-O. The deletion energy of 24 establishes that the endoanomeric interaction is of 28.3 kcal/mol, while the exoanomeric is of 30.2 kcal/mol. However, these energies are
dependent of the global disposition of the substituents
since the nOendo → σ*C-O interaction on isomer 10 is only
2.1 kcal/mol. This discrepancy led us to perform a
systematic analysis of a series of conformers to evaluate
the effect of the substituents. Thus, the series of compounds
with SRSS configuration was evaluated. On conformer 27
the endo-anomeric interaction of the hydroxyl group on
position 2 is of 3.02 kcal/mol while the exo-anomeric is of
27.4 kcal/mol. On conformer 28 the endo-anomeric
interaction is produced with 36.3 kcal/mol, but since the
antiperiplanar position is occupied by the O-H bond since
this group is acceptor of the hydrogen bond, the σH-O →
σ*C-O interaction participates with 31.2 kcal/mol. This is
in contrast with the expected result since the donor
capacity of the O-H should be smaller than that of an
unshared electron pair. On compound 29 the endoanomeric interaction for the hydroxyl at position 5 is only
5.8 kcal/mol but the σH-O → σ*C-O interaction is of 21.6
235
kcal/mol. For conformer 30 the endo-anomeric and σH-O
→ σ* C-O interactions are of 22.7 and 23.3 kcal/mol,
respectively and for conformer 31 they are of 26.0 and
28.7 kcal/mol, respectively. These values show the
importance of these interactions.16,17
On the other hand, according to Bader,18 the existence
of a bond critical point and the bond trajectory that
connects this critical point with two nuclear attractors are
a necessary and sufficient conditions for a bond to exist.
From the point of view of molecular structure, only
demonstrating its existence, it is possible to satisfactorily
prove the presence of a hydrogen bond. The molecular
scheme of conformers 24 and 10 is shown on Figure 2.
For 24, the existence of 24 nuclear attractors, 28 bond
critical points, 7 ring critical points and 2 cage critical
points satisfy the Poincaré-Hopf relationship.19,20 Due to
the symmetry, Table 1 only shows the critical points in the
electronic density of the β molecular region. As it can be
observed, the value of the laplacians associated to the bond
critical points of the hydrogen are positive which is typical
of weak bonds.
Figure 2. Critical Points associated with hydrogen bonds in
conformers 10 and 24. See Table 1.
In addition, the weak bonds are curved so for a bond
where the critical point corresponds to letter a (Figure 2),
the bond trajectory is of 3.424 a.u. While the geometric
distance that separates both nuclei is of 3.408 (r = 1.554
a.u.). For the second weak bond, the bond trajectory is of
6.306 a.u., while the geometric distance of the two nuclei
joined by the bond is of 1.740 a.u. The stronger bond
correspond to the one that closes the seven-membered ring
where the hydroxyl in anomeric position is the donor while
the weakest bond corresponds to that where the
hydroxymethyl group is the donor and the oxygen atom
that forms part of the 1,4-dioxane ring is the acceptor.
The second most stable isomer is at 0.73 kcal/mol over
the one previously described. The analysis of the
molecular structure is presented on Figure 2 and Table 1.
Again, the importance of hydrogen bonds on molecular
236
García-Jiménez et al.
J. Braz. Chem. Soc.
Table 1. Critical points related to weak interaction in compounds 24 and 10 (in au).
cpd
signature
ρ×10 2
∇2ρ×10 2
λ a×10 2
λ a×10 3
λ a×10 3
ε×10 2
24-a
24-b
24-c
24-d
24-e
24-f
24-g
10-h
10-i
10-j
10-k
10-l
10-m
10-n
3,-1
3,-1
3,+1
3,+1
3,+1
3,+1
3,+3
3,-1
3,-1
3,-1
3,+1
3,+1
3,+1
3,+1
3.68
1.22
0.65
2.17
0.97
1.12
0.65
3.08
1.09
1.42
1.61
1.04
2.25
1.05
11.0
4.27
3.12
12.9
5.00
5.05
3.37
9.92
4.36
5.01
8.40
4.63
1.35
5.05
-5.60
-0.99
-0.19
-1.78
-0.66
-0.64
0.25
-4.33
-6.73
-1.53
-1.38
-0.57
-1.87
-0.57
-5.50
-0.76
1.24
6.78
2.60
1.16
1.26
-4.18
-3.79
-1.31
3.71
0.64
7.56
0.71
2.21
6.02
2.09
7.95
3.06
4.54
1.86
-1.84
5.42
7.84
6.07
4.56
8.16
4.86
1.89
30.54
3.19
77.4
16.79
a
Eigenvalues of the Hessian at cp. See structure 24 in Figure 2 for numbering. See structure 10 in Figure 2 for numbering. Total bond Path of 24a: 3.424 au. Geometric bond length 3.408 au. difference: 1.554 au. total bond Path of 24-b: 6.306 au. Geometric bond length 4.566 au. difference:
1.74 au. total bond Path of 10-h: 3.593 au. Geometric bond length 3.564 au. difference: 0.027 au. Total bond Path of 10-i: 6.006 au. Geometric
bond length 5.564 au. difference: 0.442 au. Total bond Path of 10-j: 4.345 au. Geometric bond length 4.238 au. difference: 0.107 au.
stability is evident. The set of the molecule is 24 nuclear
attractors, 27 bond critical points, 4 ring critical points.
The hydrogen bonds identified by letters h and j (10)
are normal and when the ring is closed, the corresponding
critical points are produced. However, in electronic density
it is possible to find an unexpected interaction between
the oxygen atom at anomeric position 5 and the methylene
group of the hydroxymethyl group at position 3. This
interaction is expected for a 1,3-syn-diaxial interaction
that was not possible to observe even in the axial
methylcyclohexane.21
The energetic difference between conformer 24 of the
SRRS diasteroisomer and conformer 10 of the
diasteroisomer SRRR establishes that there is more than
99% of the former in relation to the latter and it is very
possible that a minor group of signals observed in the
spectrum is due to this isomer.
The calculations have been developed considering the
different isolated conformers at 0 K and in vapor phase. In
these conditions it would be expected that the interactions
associated with the hydrogen bond would be exacerbated
in a way where some of these interactions can be lost when
the condensed phase is reached. It can also be expected
that in solvents where the formation of hydrogen bonds is
not important conformer 24 will predominate. However,
when the solvent is capable of forming hydrogen bonds
that compete with molecular interactions, then a substantial
change in the properties of this equilibrium can be expected
and the dominating structure may not be dominating
anymore.
In a previous study we evaluated the capability of the
BP/IGLOIII//B3LYP/6-31G(d,p) method to determine
chemical shifts.22,23 We applied the same methodology to
the most abundant conformers, and the results are shown
in Figure 3.
Figure 3. 1H and 13C chemical shifts with respecy to TMS of the
global minima (isomer 24 on the left) and the conformer 10 (on the
right) at BP/IGLOIII//B3LYP/6-31G(d,p) level of theory.
It is of primer importance to find out if the most
abundant conformer descibed herein has a fundamental
role in the composition of the equilibria determined by
NMR. The absolute values of the 13C chemical shift
calculated and those determined experimentally shown a
positive average difference of 10.5 ppm for conformer 24
and of 9.9 ppm for conformer 10, regarding the 13C chemical
shifts. Thus, both conformers can contribute to the 13CNMR signals. In chloroform, it would be expected that the
conformer 24 will be observed and when using polar
solvents, these would compete with the formation of
hydrogen bonds that produce important changes.
Conclusions
From the results presented here, it can be concluded
that stabilizing effects, the stereoelectronic and the
hydrogen bonds are additive. The most stable species in
J. Mex. Chem. Soc.
Experimental and Theoretical Study of the Products from the Spontaneous Dimerization
both, molecules isolated in vapor phase and in solvents
that block the formation of intermolecular hydrogen bonds,
will be the one that presents the most stabilizing effects. In
this case, the most stable species is the 2S,5R-dihydroxy3R,6S-dihydroxymethyl-1,4-dioxane (24) conformer with
all groups in axial position where four hydrogen bonds
can be formed. A second observable conformer (10) is at
0.75 kcal/mol over the first one. The rest of the conformers
have higher energies. NBO analysis established the
importance of stereoelectronic interactions and with critical
point analysis of electronic density the nature of the
involved hydrogen bonds can be established.
Experimental
Samples of DL-Glyceraldehyde from a commerical
supplier (Fluka) were used. It must be pointed out that
DL-glyceraldehyde is crystaline and better than 97% pure
while D-glyceraldehyde is usually sold as a syrup
containing 85% of the compound and around 15% of water
(this is the approximate composition of a monohydrate)
apparently it has never been obtained in a crystalline form.
However we managed to obtain a product with more than
97% D-glyceraldehyde and 2.7% of water. The reported
purity of the sample by HPLC is 99.4%. This sample
showed an [α]D20 value of +14.92° which after one minute
turned to be +14.65.
The infrared spectra of D-gluceraldehyde was obtained
in a film over NaCl in a Bruker model tensor 27
spectrometer. The percent of free D-glyceraldehyde was
calculated as 10% ± 0.2% at 1724 cm–1 as described.7 The
percent of free DL-glyceraldehyde was estimated by
comparison of the integrated area of the carbonyl band in
relation to the integrated bands at 2956, 2924 and 2855
cm–1 corresponding to C-H strech vibration bands and then
comparing this relation with that of the value
corresponding to the relation between the integration of
the carbonyl band of D-glyceraldehyde in relation with
the integration in the region 2956 and 2855 cm –1
corresponding to C-H bands. This comparison gave a value
of 0.96% for the free aldehyde in the case of
DL-glyceraldehyde. The 1H and 13C determinations were
carried in a Varian Unity 300 instrument using perdeuterated dimethyl sulfoxide as solvent. In the case of
DL-glyceraldehyde the protons at hydroxyl group at C-1
appears as a sharp doublet (6.720 and 6.697 ppm, two
protons). In the case of the hydroxyl group at the
hydroxymethylene chain the proton appears as a sharp
triplet (centered at 4.558 ppm, two protons) both signals
do not change appreciably between 20 °C and 80 °C. The
samples were kept in a freezer at -20 °C until used and
237
were opened only to obtain the compounds just before
running the spectroscopy.
Computational methods
Full geometry optimizations (no symmetry constraints)
of all compounds were performed using the hybrid
functional B3LYP with a 6-31G(d,p) basis set. For all
compounds six d and 10f orbital functions were used.
These calculations were carried out with the Gaussian 94
Program (G94).24 NBO analyses were performed with
version 3.1 included in G94,25 and was used to evaluate
changes in hyperconjugation. The interactions between
filled and vacant orbitals represent the deviation of the
molecule from the Lewis structure and can be used as a
measure of delocalization.16,17 Wave functions were used
to compute AIM atomic energies using the AIMPAC set of
programs.26
The 1H and 13 C chemical shifts were calculated
according to the proposed sum-over-states density
functional perturbation theory (SOS-DFTPT) 27 as
implemented in a modified deMon-KS program.28 For the
chemical shifts, the semilocal excange of Perdew and
Wang29 and the correlation functional by Perdew (PP)30
was used. This selection follows the suggestion made by
the authors of SOS-DFTPT that this functional provides
the best overall results for the simultaneous calculation of
chemical shifts and spin-spin coupling constants. For the
evaluation of the first-order corrections to the Kohn-Sham
orbitals, the Local 1 approximation (LOC1) was used. The
individual Gauge for Localized Orbitals (IGLO) was
selected to approach the gauge problem, and the IGLO-III
of Kutzelnigg et al.31 was used as the basis set in the
chemical shifts calculations. A fine grid with an extra
iteration after achieving self-consistency was performed.
Chemical shifts presented in this work are relative to
tetramethyl silane (TMS).
Acknowledgments
We aknowledge to Isabel Chavez, Hector Ríos and
María de las Nieves Zavala for the nuclear magnetic
resonance determination. We are grateful to the Dirección
General de Servicios de Cómputo Académico, Universidad
Nacional Autónoma de México DGSCA, UNAM, to
Consejo Nacional de Ciencia y Tecnología (CONACYT)
for financial support via grant 40390-Q, to Dirección
General de Asuntos del Personal Académico (DGAPA) via
Grant No. IN-7200 and to Rebeca López García who revised
the English version of this manuscript.
238
García-Jiménez et al.
References
J. Braz. Chem. Soc.
22. Cuevas, G.; Juaristi, E.; Vela, A.; J. Mol. Struct. (Theochem)
1997, 418, 231.
1. Richard, M.; Krishna, N.I. In Biochemistry & Molecular Biology
of Plants; Buchanan, B.; Gruissem, W.; Jones, R., eds., 2000
American Society of Plant Physiologists: Rockville, Maryland,
USA, Ch. 12, p.610-611.
23. Cortés, F.; Cuevas, G.; Tenorio, J.; Rochin, A.L.; Rev. Soc.
Quim. Méx. 2000, 44, 7.
24. Gaussian 94, Revision D.4, Frisch, M. J.; Trucks, G.W.;
Schlegel, H.B.; Gill, P.M.W.; Johnson, B.G.; Robb, M.A.;
2. Timberlake, K.C.; General Organic and Biological Chemistry;
Cheeseman, J.R.; Keith, T.; Petersson, G.A.; Montgomery, J.A.;
The Benjamin Cummings Publishing: San Francisco, CA, USA,
Raghavachari, K.; Al-Laham, M.A.; Zakrzewski, V.G.; Ortiz,
2002, Ch. 16.
J. V.; Foresman, J.B.; Cioslowski, J.; Stefanov, B.B.;
3. Juaristi, E.; Introduction to Stereochemistry and
Conformational Analysis, Wiley: New York, 1994.
Nanayakkara, A.; Challacombe, M.; Peng, C.Y.; Ayala, P.Y.;
Chen, W.; Wong, M.W.; Andres, J.L.; Replogle, E.S.; Gomperts,
4. Wohl, A.; Ber. 1889, 31, 2394.
R.; Martin, R.L.; Fox, D.J.; Binkley, J.S.; Defrees, D.J.; Baker,
5. Wohl, A.; Neuberg, C.; Ber. 1900, 33, 3095.
J.; Stewart, J.P.; Head-Gordon, M.; Gonzalez, C.; Pople, J.A.,
6. Varonjan, Y. A.; Harty-Majors, S.; Ismail Ashraf, A.; Carboh.
Gaussian, Inc.: Pittsburgh, PA, 1995.
Res. 1999, 318, 20.
7. Swenson, C.A.; Barker, R.; Biochemistry 1971, 16, 3151.
8. Arreguin, B.; Taboada, J.; J. Crom. Sci. 1970, 8, 187.
9. Cram, D.J.; Abd Elhafez, F.A.; J. Am. Chem. Soc. 1952, 74,
5828.
10. Chapman, D.M.; Hester, R.E.; J. Phys. Chem. A. 1997, 101,
3382.
11. Martínez Mayorga, K.; Cortés, F.; Leal, I.; Reyna, V.; Quintana,
D.; Antúnez, S.; Cuevas, G.; Arkivoc. 2003, XI, 132.
12. Juaristi, E.; Cuevas, G.; The Anomeric Effect, CRC press: Boca
Raton, FL, 1994.
25. NBO 3.1., Glendening, E. D.; Reed, A. D.; Carpenter, J. E.;
Weinhold, F. Theoretical Chemistry Institute, University of
Wisconsin: Madison, WI, 1993.
26. Biegler-Koing, F. W.; Bader, R. F. W.; Tang, T. H.; J. Comput.
Chem. 1982, 3, 317.
27. Malkin, V.G.; Malkina, O.L.; Casida, M.E.; Salahub, D.R.; J.
Am. Chem. Soc. 1994, 116, 5898; Malkin, V.G.; Malkina,
O.L.; Eriksson, L.A.; Salahub, D.R. In Modern Density
Functional Theory. A Tool for Chemistry; Seminario, J.M.;
Politzer, P., eds., Elsevier: Amstardam, 1995.
28. St-Amant, A.; Salahub, D.R.; Chem. Phys. Lett. 1990, 169,
13. Juaristi, E.; Cuevas, G.; Tetrahedron, 1992, 48, 5019.
387; Salahub D.R.; Castro, M.E.; Proynov, E.I.; Relativistic
14. Cuevas, G.; Juaristi, E.; Vela, A.; J. Phys. Chem. A 1999, 103,
and Electron Correlation Effects in Molecules and Solids, Vol.
932; Cuevas, G.; Juaristi, E.; J. Am. Chem. Soc. 2002, 124,
318, of NATO ASI Series B: Physics, Plenum Press: New York,
13088; Martínez-Mayorga, K.; Juaristi, E.; Cuevas, G.; J. Org.
1994, p. 411; Salahub, D.R.; Castro M.E.; Fournier, R.;
Chem. 2004, 69 7266.
Calaminici, P.; Godbout, N.; Goursot, A.; Jamorski, C.;
15. Alabugin, I. V.; Manoharan, M.; Peabody, S.; Weinhold, F.; J.
Am.Chem. Soc. 2003, 125, 5973.
16. Cortés, F.; Tenorio, J.; Collera, O.; Cuevas, G.; J. Org. Chem.
2001, 66, 2918.
17. Cuevas, G.; Tenorio, J.; Cortés, F.; Rev. Soc. Quim. Méx. 2000,
44, 42.
18. Bader, R.F.W.; Atoms in Molecules, a Quantum Theory,
Kobayashi, H.; Martinez, A.; Papai, I.; Proynov, E.; Russo, N.;
Sirois, S.; Ushio, J.; Vela, A. In Theoretical and Computational
Approaches to Interface Phenomena, Sellers, H.; Golab, J.T.,
eds., Plenum Press: New York, 1995, vol. 9, p. 187.
29. Perdew, J.P.; Wang, Y.; Phys. Rev. B 1986, 33, 8800.
30. Perdew, J.P.; Phys. Rev. B 1986, 33, 8822; ibid. 1986, 34,
7406.
Clerendon Press: Oxford, 1990; Bader, R.F.W. In Encyclopedia
31. Kultzelnigg, W.; Fleischer, U.; Schindler, M.; NMR-Basic
of Computational Chemistry; Schleyer, P.v.R., ed., 1998, John
Principles and Progress, Springer-Verlag: Heidelberg, vol.
Wiley & Sons: New York, p. 64.
33, 1990, p. 165.
19. Cuevas, G.; J. Am. Chem. Soc. 2000, 122, 692.
20. Madrid, G.; Rochín, A.; Juaristi, E.; Cuevas, G.; J. Org. Chem.
2001, 66, 2925.
21. Cortés-Guzmán, F.; Hernández-Trujillo, J.; Cuevas, G.; J. Phys.
Chem. A. 2003, 44, 9253z.
Received: November 23, 2004
Published on the web: May 10, 2005